# SARS-CoV-2-Derived RNA Fragment Induces Myocardial Dysfunction via siRNA-like Suppression of Mitochondrial ATP Synthase

## TL;DR

A specific RNA fragment from SARS-CoV-2 can impair heart cell function by suppressing a key mitochondrial gene, leading to heart failure-like effects.

## Contribution

Discovery of a SARS-CoV-2 RNA fragment that mimics siRNA to suppress ATP5A, linking viral RNA to mitochondrial dysfunction in heart cells.

## Key findings

- A 19-nucleotide RNA fragment from SARS-CoV-2 shares sequence homology with ATP5A and associates with AGO2.
- This RNA fragment suppresses ATP5A expression, impairing oxidative phosphorylation and causing heart failure-like phenotypes in cardiomyocytes.
- Exosome-mimetic delivery of the RNA fragment reproduces ATP5A suppression, suggesting a potential mechanism for myocardial injury.

## Abstract

Myocardial injury is a critical determinant of prognosis in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection; however, its underlying mechanisms remain incompletely understood. In this study, we examined the effects of SARS-CoV-2-derived RNA fragments on human cardiomyocytes. We identified a 19-nucleotide sequence within the viral genome that shares complete sequence homology with the human F1F0 ATP synthase subunit alpha gene (ATP5A). This sequence was found to associate with Argonaute 2 (AGO2) and downregulate ATP5A expression via a mechanism analogous to RNA interference. Consequently, oxidative phosphorylation was suppressed in cardiomyocytes, leading to impaired myocardial maturation and the emergence of heart failure-like phenotypes. Notably, exosome-mimetic liposomal delivery of this RNA fragment to cardiomyocytes reproduced the ATP5A-suppressive effect. These findings suggest that SARS-CoV-2-derived RNA fragments may contribute to myocardial injury through the siRNA-like modulation of mitochondrial gene expression. Further validation in animal models and patient-derived materials is warranted.